Multi-ligand drug conjugates and uses thereof

Abstract

A conjugate compounds or pharmaceutically acceptable salt thereof, comprises a payload and two or more kinds of cell-interacting molecules. The cell-interacting molecules are ligands capable of specifically binding to a cell surface receptor. A method of treating diseases, comprises delivering a payload to a subject.

1 - 55 . (canceled) 
     
     
         56 . A conjugate compound or a pharmaceutically acceptable salt thereof, comprising
 a payload; and   a plurality of cell-interacting molecules comprising first and second cell-interacting molecules,   wherein
 the first cell-interacting molecule comprises a first ligand capable of specifically binding to a first cell surface receptor, and 
 the second cell-interacting molecule comprises
 (a) a second ligand capable of specifically binding to a second cell surface receptor; or 
 (b) an endocytosis molecule capable of mediating endocytosis, 
 
 wherein the first and second surface receptors are selected from the group consisting of a transferrin receptor (TFR), a low-density lipoprotein receptor (LDLR), a uric acid kinase receptor, a tumor necrosis factor receptor (TNFR), a somatostatin-14 (SST-14) receptor, a luteinizing hormone releasing hormone (LHRH) receptor, and a transient receptor potential cation channel subfamily V member 6 (TRPV6), and 
 the endocytosis molecule is selected from the group consisting of folate and analogs thereof, and a cell-penetrating peptide, 
 and wherein the first and second cell surface receptors are different from each other; 
   wherein the payload is selected from the group consisting of a small molecule compound, a nucleotide, a peptide, and a protein, and wherein the payload is conjugated with at least one of the cell-interacting molecules directly or via a linker.   
     
     
         57 . The conjugate compound of  claim 56 , or a pharmaceutically acceptable salt thereof, wherein the payload is conjugated with at least one of the cell-interacting molecules via a linker. 
     
     
         58 . The conjugate compound of  claim 56 , or a pharmaceutically acceptable salt thereof, wherein the plurality of cell-interacting molecules comprise a first ligand capable of specifically binding to a first cell surface receptor, and a second ligand capable of specifically binding to a second cell surface receptor. 
     
     
         59 . The conjugate compound of  claim 58 , or a pharmaceutically acceptable salt thereof, wherein the payload is conjugated with the first ligand, and the first ligand is conjugated with the second ligand. 
     
     
         60 . The conjugate compound of  claim 59 , or a pharmaceutically acceptable salt thereof, wherein the first ligand is conjugated with the second ligand via a spacer. 
     
     
         61 . The conjugate compound of  claim 58 , or a pharmaceutically acceptable salt thereof, wherein the payload is conjugated with the first ligand via a first linker, and the payload is conjugated with the second ligand via a second linker. 
     
     
         62 . The conjugate compound of  claim 56 , or a pharmaceutically acceptable salt thereof, wherein the payload is a small molecule compound that is auristatins or any derivatives thereof. 
     
     
         63 . The conjugate compound of  claim 56 , or a pharmaceutically acceptable salt thereof, wherein the first ligand and the second is independently selected from the group consisting of a peptide. 
     
     
         64 . The conjugate compound of  claim 63 , or a pharmaceutically acceptable salt thereof, wherein the peptide comprises the amino acid sequence selected from the group consisting of SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, and a homologous peptide having at least 70% amino acid sequence homology to any of SEQ ID NOs: 15-18, wherein the homologous peptide is a functional equivalent of any one of the peptides of SEQ ID NOs: 15-18. 
     
     
         65 . The conjugate compound of  claim 58 , or a pharmaceutically acceptable salt thereof, further comprising a third ligand capable of specifically binding to a third cell surface receptor. 
     
     
         66 . The conjugate compound of  claim 65 , or a pharmaceutically acceptable salt thereof, wherein the first, second and third cell surface receptors are different from one another. 
     
     
         67 . The conjugate compound of  claim 66 , or a pharmaceutically acceptable salt thereof, wherein the first, second and the third ligand is independently selected from the group consisting of a peptide, and wherein the third cell surface receptor is selected from the group consisting of a transferrin receptor (TFR), a low-density lipoprotein receptor (LDLR), a uric acid kinase receptor, a tumor necrosis factor receptor (TNFR), SST-14 receptor, LHRH receptor, and TRPV6. 
     
     
         68 . The conjugate compound of  claim 56 , or a pharmaceutically acceptable salt thereof, wherein the plurality of cell-interacting molecules comprise the first ligand capable of specifically binding to a cell surface receptor and the endocytosis molecule. 
     
     
         69 . The conjugate compound of  claim 68 , or a pharmaceutically acceptable salt thereof, wherein the first endocytosis molecule is a cell-penetrating molecule. 
     
     
         70 . The conjugate compound of  claim 56 , or a pharmaceutically acceptable salt thereof, wherein the cell-penetrating peptide comprises the amino acid sequence of SEQ ID NO: 19 or SEQ ID NO: 20. 
     
     
         71 . The conjugate compound of  claim 56 , or a pharmaceutically acceptable salt thereof, wherein the plurality of cell-interacting molecules comprise a first endocytosis molecule and a second endocytosis molecule, wherein the first endocytosis molecule is the same as the second endocytosis molecule. 
     
     
         72 . The conjugate compound of  claim 56 , or a pharmaceutically acceptable salt thereof, wherein the plurality of cell-interacting molecules comprise a first endocytosis molecule and a second endocytosis molecule, wherein the first endocytosis molecule is different from the second endocytosis molecule. 
     
     
         73 . The conjugate compound of  claim 71 , or a pharmaceutically acceptable salt thereof, further comprising a third cell-interacting molecule, wherein the third cell-interacting molecule is an endocytosis molecule. 
     
     
         74 . A pharmaceutical composition comprising the conjugate compound of  claim 56 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         75 . A method for treating a disease in a subject, comprising administering to the subject a therapeutically effective amount of a conjugate compound comprising
 a payload; and   a plurality of cell-interacting molecules comprising first and second cell-interacting molecules,   wherein
 the first cell-interacting molecule comprises a first ligand capable of specifically binding to a first cell surface receptor, and 
 the second cell-interacting molecule comprises
 (a) a second ligand capable of specifically binding to a second cell surface receptor; or 
 (b) an endocytosis molecule capable of mediating endocytosis, 
 
 wherein the first and second surface receptors are selected from the group consisting of a transferrin receptor (TFR), a low-density lipoprotein receptor (LDLR), a uric acid kinase receptor, a tumor necrosis factor receptor (TNFR), a somatostatin-14 (SST-14) receptor, a luteinizing hormone releasing hormone (LHRH) receptor, and a transient receptor potential cation channel subfamily V member 6 (TRPV6), and 
 the endocytosis molecule is selected from the group consisting of folate and analogs thereof, and a cell-penetrating peptide, 
 and wherein the first and second cell surface receptors are different from each other; 
   wherein the payload is selected from the group consisting of a small molecule compound, a nucleotide, a peptide, and a protein, and wherein the payload is conjugated with at least one of the cell-interacting molecules directly or via a linker.